1. Field of the Invention
The present invention relates to a preparation process of polyester by ring-opening polymerization of a cyclic ester compound. More particularly, the invention relates to a reproducible and consistent process for conducting ring-opening polymerization of a cyclic ester compound to prepare polyesters of a desired molecular weight which include polyhydroxycarboxylic acids such as polyglycolic acid, polylactic acid, polycaprolactone, polypropiolactone, polybutyrolactone and polyvalerolactone and copolymers thereof.
2. Related Art of the Invention
Polyesters including polyhydroxycarboxylic acids such as polyglycolic acid, polylactic acid, polycaprolactone, polypropiolactone polybutyrolactone and polyvalerolactone and copolymers thereof can be prepared by ring-opening polymerization of cyclic ester compounds such as lactide, glycolide and .epsilon.-caprolactone. These polyester can be decomposed with ease by water and enzyme and thus have been focused attention as biodegradable polymers.
Particularly, polylactic acid, polyglycolic acid and a lactic acid/glycolic acid copolyester which are prepared by ring-opening polymerization of lactide, glycolide and a mixture of these compounds, respectively, can be decomposed and absorbed with extreme ease in a living body. Consequently, these compounds are also referred to as bioabsorbable polymers and are used for medical materials such as surgical suture, matrix resin of slow release microspheric drugs and an absorbable plate for bonesetting. Further, in a field other than medical use, application to various formed materials such as films and sheets is under development. In any cases, it is desired to have satisfactory mechanical strength and hydrolyzability for respective used and thus required to maintain a certain level of mechanical strength for a prescribed period and thereafter to decompose quickly. In order to meet these characteristics, it is essentially important to limit the molecular weight of polyesters to a specific range, and additionally to restrict the copolymer composition to a certain range.
Various processes have been known for the preparation of cyclic ester compounds. As a general process, hydroxycarboxylic acid which corresponds to the desired cyclic ester compound is subjected to dehydration ring-closure. For example, lactide or glycolide is individually prepared by heating lactic acid or glycolic acid under reduced pressure to conduct dehydration condensation and by further heating the resultant lactic acid oligomer or glycolic acid oligomer to form a cyclic dimer through ring-closure. The cyclic ester compound thus obtained is usually purified by recrystallizing from a solvent such as ethyl acetate and used as a purified cyclic ester compound such as pure glycolide or pure lactide.
Preparation processes of polyesters such as polyglycolic acid, polylactic acid and a glycolic acid/lactic acid copolyester by ring-opening polymerization of these cyclic ester compounds have been described in, for example, Japanese Laid-Open Patent Sho 63-017929, U.S. Pat. Nos. 4,850,763 and 5,041,529. In these processes, ring-opening polymerization is carried out by heating glycolide and/or lactide in the presence of a stannous octoate catalyst and higher aliphatic alcohol such as lauryl alcohol or, hydroxycarboxylic acid such as lactic acid.
U.S. Pat. No. 3,442,871 has disclosed a preparation process of polyglycolic acid by polymerization of glycolide in the presence of prescribed amounts of a stannous chloride catalyst and an alcohol initiator (polymerization regulator) which is of from non-benzenoid unsaturation and free of reactive groups other than alcoholic hydroxyl group.
In the preparation of polyesters by ring-opening polymerization of cyclic ester compounds, regulation of the polyester molecular weight to a desired value has conventionally been considered very difficult. U.S. Pat. No. 3,442,887 above has described that the viscosity, that is, molecular weight of the polymer formed can be controlled by adjusting the amount of the initiator. However, the regulation of molecular weight (viscosity) in said patent merely means that, as seen in the examples, a low molecular weight polymer is formed by using a larger amount of the initiator and a high molecular weight polymer is formed in the presence of a smaller amount of the initiator. The results of these examples do not mean consistent production of polymers having a desired molecular weight.
According to the results of a careful trace conducted by the present inventors, several batches of the polymerization reaction under the same catalyst amount, the same initiator amount, the same reaction temperature and the same reaction time led to a significant dispersion on the molecular weight of polymers formed and some of the polymers caused difficulty in application to spinning and other processing. The fact that polymers having a constant molecular weight cannot be obtained means an impossibility of so-called targeting, that is, "preparation of polymers having an aimed molecular weight" which is a most important subject on the preparation of polymers in the invention.
Even though the catalyst amount, initiator amount, reaction temperature, reaction time and conversion rate are individually controlled under a certain condition, polymers having a constant molecular weight cannot be obtained because the polymerization reaction is greatly affected by the impurities contained in the cyclic ester monomer.
Impurities which give an adverse effect on the polymerization reaction include, for example, moisture, free carboxylic acids, metals and aldehydes. Impurities such as metals and aldehydes give a relatively small influence on the polymerization reaction and, as a result of recent advances in purification technique, can be reduced with ease to an amount which does not give an adverse effect on the polymerization reaction. Moisture contained in the monomer can also be removed with ease in the purification and drying step conducted immediately before polymerization. On the other hand, free carboxylic acid contained in the monomer gives a great influence on the polymerization reaction. Representative free carboxylic acids contained in the cyclic ester compound include hydroxycarboxylic acids used in the preparation of the cyclic ester compound, for example, lactic acid in the case of lactide and glycolic acid in the case of glycolide; straight chain oligomer of hydroxycarboxylic acid which is an intermediate product of the cyclic ester compound; and hydroxycarboxylic c acid formed from the cyclic ester compound as a result of hydrolysis due to some cause.
According to the information of the present inventors, it has been known that, in the preparation of polyester having a molecular weight of, for example, tens of thousands.about.hundreds of thousands, molecular weight of the formed polyester widely fluctuates in the presence of merely tens.about.100 ppm of free carboxylic acid. However, it is presently impossible to completely remove a free carboxylic acid from the monomer.
Various designs have conventionally been carried out in the preparation of the cyclic ester compounds. For example, Japanese Laid-Open Patent Sho 59-148777 has disclosed a purification process of glycolide which comprises heat-melting crude glycolide, dropwise adding the molten glycolide into an organic solvent maintained with stirring at a temperature of from 100.degree. C. to less than the boiling point to form a glycolide suspension, successively cooling the suspension to 0.degree..about.20.degree. C., and separating and drying pure glycolide.
Further, Japanese Laid-Open Patent Sho 62-270574 has disclosed a purification process of glycolide comprising dissolving glycolide in an organic solvent, adding alumina to the solution obtained, stirring the resultant slurry for 1.about.60 minutes, successively removing alumina by filtration and evaporating the solvent from the filtrate.
However, even though purification of glycolide is repeated several times according to these known processes, it is difficult to remove free carboxylic acid and other impurities to such an extent that these impurities give no adverse effect on the polymerization reaction. The extent of purification naturally leads to dispersion in the batch to batch amount of the impurities contained in the purified cyclic ester compounds. Further, in the case of readily hydrolyzable cyclic ester compounds such as lactide and glycolide in particular, even extremely purified compounds usually cause reduction of purity during storage because a free carboxylic acid such as a hydroxycarboxylic acid is formed as a result of hydrolysis by environmental moisture. Additionally, the amount of the hydroxycarboxylic acid generated during storage cannot be anticipated at all.
Consequently, when high molecular weight polyesters are prepared by ring-opening polymerization of the cyclic ester compounds, an unexpected dispersion is developed in the molecular weight of formed polyesters and leads to a serious problem on the production in industry. In order to prepare polyesters having a desired molecular weight, it is essentially important to measure immediately before use the amount of a free carboxylic acid such as a hydroxycarboxylic acid contained in the cyclic ester compounds which are raw material monomers.
However, it has not yet been known to accurately and simply estimate the amount of a free carboxylic acid contained in the readily hydrolyzable cyclic ester compounds in particular.
The amount of the free carboxylic acid contained in the cyclic ester compounds can be estimated in accordance with JIS K-0070, a method for testing an acid value or a hydroxyl value of chemical products. That is, the acid value is estimated by completely dissolving a sample in 100 cm.sup.3 of an ether/ethyl alcohol mixture, containing phenolphthalein as an indicator and titrating the solution with a 0.1N potassium hydroxide solution in ethanol. The hydroxyl value is estimated by acetylating a sample with acetic anhydride and successively titrating the resulting solution with a 0.5N potassium hydroxide solution in ethanol, using phenolphthalein as an indicator.
These methods, however, are not suited for estimating trace quantities of free carboxylic acid contained in the readily hydrolyzable cyclic ester compounds. That is, the following problems are encountered in the acid value estimation.
(1) The cyclic ester compound is hydrolyzed by the moisture contained in the solvent for use in the estimation and the amount of free carboxylic acid increases with the lapse of time. Consequently, the quantity of titration cannot be constant. PA1 (2) In order to estimate traces (about a few hundred ppm) of free carboxylic acid contained in the cyclic ester compounds, it is required to dissolve 10.about.20 g of a sample in a solvent. However, dissolving operation is difficult because solubility of the sample is low. Similarly to the above case, the cyclic ester compounds are liable to hydrolyze also in the course of hydroxyl value measurement and to cause transesterification with acetic anhydride. These side reactions inhibit accurate estimation. PA1 (1) The titrating solution of potassium methoxide in methanol having a high concentration of 0.01N cannot estimate free carboxylic acid equivalent to less than one drop of the titrating solution. For example, the difference between 100 ppm and 50 ppm of free carboxylic acid contents cannot be detected. PA1 (2) On the other hand, a titrating solution having a low concentration develops merely a faint color of the indicator and the hue varies delicately. Consequently, the end point of titration is difficult to judge. PA1 (3) Acids are generated by hydrolysis of the cyclic ester compounds due to traces of moisture contained in the solvent or atmosphere and measured values cause time dependent variation in the course of titrating operation.
Japanese Laid-Open Patent HEI 1-146924 has disclosed a preparation process of polymeric lactide comprising copolymerizing a meso-lactide monomer having a free acid content of less than 1 mg equivalent/kg lactide through a known method with another monomer or lactide having a free acid content of optionally less than 1 mg equivalent/kg. This invention describes the following quantitative analytical method for impurities in lactide.
The method is to dissolve lactide in anhydrous methanol and titrate with a 0.01N potassium methoxide solution in methanol by using phenolphthalein as an indicator. However, trace quantity of free carboxylic acid could not be measured by the method with good reproducibility because of the following reasons.
Consequently, it is difficult to estimate traces of the free carboxylic acid with good reproducibility.
Japanese Patent Laid-Open Sho 60-144325 has described a preparation process of polyglycolic acid wherein glycolide having a melting point of 81.degree. C. or more and APttA value of 150 or less after heat-melting at 200.degree. C. for 3 minutes is selected for the raw material. The method can judge whether or not the glycolide to be used is suited for polymerization to obtain polyglycolic acid having an inherent viscosity of 0.9 dl/g or more. However, it is quite impossible to control the molecular weight of polyglycolic acid within the desired range by means of melting point and APHA value a lone.
Additionally, the present inventors prepared polylactic acid or polyglycolic acid by conducting ring-opening polymerization of lactide having a free acid content of 1 mg equivalent/kg or less or glycolide having a melting point of 81.degree. C. or more and an APHA value of 150 or less. However, the molecular weight of polyester thus obtained still exhibited considerable dispersion for each batch and it is was difficult to obtain polyester having a molecular weight controlled within a prescribed range. Thus, the method was not always satisfactory.
As described above, the cyclic ester compounds are liable to undergo ring-opening by traces of moisture, though purified and stored under tight seal, and thus liable to generate new carboxylic acid. When free carboxylic acid is contained as impurities in the cyclic ester compounds even though in a trace amount, it becomes difficult to consistently prepare polyester having a desired molecular weight.